Journal
PLOS GENETICS
Volume 9, Issue 3, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1003379
Keywords
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Categories
Funding
- National Human Genome Research Institute (NHGRI)
- NHGRI ARRA supplements
- NHGRI PAGE program [U01HG004803, U01HG004802, U01HG004790]
- National Heart, Lung, and Blood Institute [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, HL54471, HL54472, HL54473, HL54495, HL54496, HL54497, HL54509, HL54515, 2 R01 HL55673-12, HL087647]
- National Cancer Institute [R37CA54281, R01 CA63, P01CA33619, U01CA136792, U01CA98758]
- NIH [DK078150, TW05596, HL085144, DK062370, DK072193, DK093757]
- U.S. Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221]
- PAGE Coordinating Center [U01HG004801-01]
- National Institutes of Mental Health
- National Health Research Institutes [PH-100-SP-01, BS-094-PP-01, PH-100-PP-03]
- National Taiwan University Hospital [NTUH.98-N1266, NTUH100-N1775, NTUH101-N2010, NTUH101-N, VN101-04, NTUH 101-S1784]
- NSC [96-2314-B-002-152, 101-2325-002-078, NSC 98-2314-B-075A-002-MY3]
- National Science Council of Taiwan [NSC96-2314-B-002-151, NSC98-2314-B-002-122-MY2, NSC 100-2314-B-002-115]
- Taichung Veterans General Hospital, Taichung, Taiwan [TCVGH-1013001C, TCVGH-1013002D]
- hospital districts of Pirkanmaa
- hospital districts of South Ostrobothnia
- hospital districts of Central Finland
- National Institute for Health and Welfare
- Finnish Diabetes Association
- Ministry of Social Affairs and Health in Finland
- Academy of Finland [129293, 117844, 40758, 211497, 118590, 102318, 123885, 77299, 124243]
- Commission of the European Communities
- Directorate C-Public Health [2004310]
- Finland's Slottery Machine Association
- Kuopio University Hospital from Ministry of Health and Social Affairs [5254]
- Finnish Funding Agency for Technology and Innovation [40058/07]
- Nordic Centre of Excellence on Systems Biology in Controlled Dietary Interventions and Cohort Studies, SYSDIET [070014]
- Finnish Diabetes Research Foundation
- Yrjo Jahnsson Foundation [56358]
- Sigrid Juselius Foundation
- Juho Vainio Foundation
- TEKES [40058/07, 70103/06]
- Ministry of Education and Culture of Finland [627]
- Kuopio University Hospital [5207]
- Finnish Heart Association
- Paivikki and Sakari Sohlberg Foundation
- European Commission [LSHM-CT-2004-005272]
- City of Kuopio
- Social Insurance Institution of Finland [4/26/2010]
- Finnish Foundation for Cardiovascular Research
- University of Eastern Finland
- University of Tromso
- Norwegian Research Council [185764]
- [U01HG004798]
- [U01HG004801]
- [RR20649]
- [ES10126]
- [DK56350]
- [1Z01-HG000024]
- Academy of Finland (AKA) [211497, 211497] Funding Source: Academy of Finland (AKA)
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Genome-wide association studies (GWAS) have identified similar to 100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P, 1610 24 in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies.
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